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      Structure-function relationships in cellular copper control

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      Date
      2009
      Author
      Zhang, Limei
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      Abstract
      X-ray absorption spectroscopy and computational chemistry have been used to probe the structure of biomolecules involved in cellular copper homeostasis. X-ray absorption spectroscopy shows that copper chaperones involved in cytochrome c oxidase assembly bind Cu(I) with trigonal coordination environments in poly-copper thiolate clusters, but the number of coppers in these clusters remains unclear. X-ray absorption spectroscopy of the metal-sensing transcription factor-1 from Drosophila melanogaster and metallothionein from Saccharomyces cerevisiae with stoichiometries of four or less shows a tetracopper cluster in an all-or-none manner in these molecules. These results suggest that cooperative binding of copper to form tetracopper clusters may be a common mechanism employed by copper control molecules. The active site structure of the novel copper-sensitive repressor CsoR in Mycobacterium tuberculosis binds copper in a trigonal coordination geometry with two sulfur and one nitrogen donors according to X-ray absorption spectroscopy results. Molecular dynamics simulations of both apo- and Cu-bound CsoR reveal local conformational changes in CsoR upon copper binding, which suggests multiple possible mechanisms of Cu-dependent transcriptional regulation by CsoR. Finally, X-ray absorption spectroscopy and X-ray fluorescence imaging have been used to understand the molecular basis of a promisng new treatment for Wilson’s disease (a genetic disorder of Cu homeostasis) using tetrathiomolybdate. Overall, the results presented provide an essential structural basis for understanding copper homeostasis in living cells.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Geological Sciences
      Program
      Geological Sciences
      Supervisor
      George, Graham N.
      Committee
      Nichol, Helen; Ellis, Thomas; Blackburn, Ninian J.; Pickering, Ingrid J.
      Copyright Date
      2009
      URI
      http://hdl.handle.net/10388/etd-06042009-075216
      Subject
      density functional theory
      X-ray absorption spectroscopy
      cellular Cu control
      molecular dynamics
      metallothionein
      Cu chapterone
      CsoR
      MTF-1
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